Pancreatic Acinar-Specific Overexpression of Reg2 Gene Offered No Protection Against Either Experimental Diabetes or Pancreatitis in Mice.

Abstract

Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3␦] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet ␤-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3␣ increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased ␤-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 promoter (Ela-Reg2) to develop an acinar cell-specific overexpression of the Reg2 gene. Western blot analysis, real-time PCR, and immunohistochemistry revealed barely detectable levels of endogenous Reg2 in the pancreas of normal wild-type mice and increased Reg2 levels in the pancreas of Ela-Reg2 mice that were similar to or higher than Reg2 levels induced in experimental diabetes or pancreatitis. Compared with wild-type littermates, growth, blood glucose and insulin levels, and glucose tolerance were normal in Ela-Reg2 mice; pancreatic histology revealed no change in endocrine or exocrine tissues. Acinar-specific overexpression of the Reg2 gene offered no protection against streptozotocin-induced ␤-cell damage and diabetes, in hyperglycemia and weight loss, and no advantage in restoring glucose homeostasis and islet function within 3 mo. Furthermore, serum amylase level and pancreatic histochemistry showed that Reg2 overexpression did not protect acinar cells against caerulein-induced acute pancreatitis. In contrast to INGAP or Reg3␤, exocrine overexpression of Reg2 offered no protection to the endocrine or exocrine pancreas, indicating clear subtype specificities of the Reg family of proteins.caerulein; immunohistochemistry; pancreatic islets; streptozotocin; transgenic mice REG PROTEINS CONSTITUTE a conserved family of seven members (Reg1, Reg2, Reg3␣, Reg3␤, Reg3␦, Reg3␥, and Reg4) in rodents; their production in the pancreas (including the islets of Langerhans) was induced upon endocrine ␤-cell or exocrine acinar cell damage (2,11,14,15). While some of these proteins [Reg1 and islet neogenesis-associated protein (INGAP or Reg3␦)] have been implicated in promoting ␤-cell replication and/or neogenesis in in vivo studies in transgenic and knockout mice (24 -26, 32), the roles of the other five proteins have not been well characterized. A unique seven-amino acid insertion (QVAEEDE) near its NH 2 terminus distinguishes Reg2 (found only in mice and hamsters) from other Reg proteins (4, 29). Results from a recent dual-labeled immunohi...

Dimorphic autoantigenic and protective effects of Reg2 peptide in the treatment of diabetic β‐cell loss

“…In our early research, overexpression of Reg2 ameliorated mitochondrial and endoplasmic reticulum (ER)‐stress‐induced cell death in MIN6 cells . In vivo, however, acinar‐specific overexpression of Reg2 provided no protection in STZ‐induced diabetic mice, leading to doubt that insufficient protein synthesis and secretion may be the key . Recently, we found that islet‐specific Reg2 knockout in aged and obese mice caused the diabetic conditions to deteriorate, suggesting that Reg2 expression is required for pancreatic islet compensation .…”